Supported exercise TrAining for Men wIth prostate caNcer on Androgen deprivation therapy (STAMINA): study protocol for a randomised controlled trial of the clinical and cost-effectiveness of the STAMINA lifestyle intervention compared with optimised usual care, including internal pilot and parallel process evaluation.

BACKGROUND: UK national clinical guidance recommends that men with prostate cancer on androgen deprivation therapy are offered twice weekly supervised aerobic and resistance exercise to address iatrogenic harm caused by treatment. Very few NHS trusts have established adequate provision of such services. Furthermore, interventions fail to demonstrate sustained behaviour change. The STAMINA lifestyle intervention offers a system-level change to clinical care delivery addressing barriers to long-term behaviour change and implementation of new prostate cancer care pathways. This trial aims to establish whether STAMINA is clinically and cost-effective in improving cancer-specific quality of life and/or reducing fatigue compared to optimised usual care. The process evaluation aims to inform the interpretation of results and, if the intervention is shown to benefit patients, to inform the implementation of the intervention into the NHS. METHODS: Men with prostate cancer on androgen deprivation therapy (n = 697) will be identified from a minimum of 12 UK NHS trusts to participate in a multi-centre, two-arm, individually randomised controlled trial. Consenting men will have a 'safety to exercise' check and be randomly allocated (5:4) to the STAMINA lifestyle intervention (n = 384) or optimised usual care (n = 313). Outcomes will be collected at baseline, 3-, 6- and 12-month post-randomisation. The two primary outcomes are cancer-specific quality of life and fatigue. The parallel process evaluation will follow a mixed-methods approach to explore recruitment and aspects of the intervention including, reach, fidelity, acceptability, and implementation. An economic evaluation will estimate the cost-effectiveness of the STAMINA lifestyle intervention versus optimised usual care and a discrete choice experiment will explore patient preferences. DISCUSSION: The STAMINA lifestyle intervention has the potential to improve quality of life and reduce fatigue in men on androgen deprivation therapy for prostate cancer. Embedding supervised exercise into prostate cancer care may also support long-term positive behaviour change and reduce adverse events caused by treatment. Findings will inform future clinical care and could provide a blueprint for the integration of supervised exercise and behavioural support into other cancer and/or clinical services. TRIAL REGISTRATION: ISRCTN 46385239, registered on 30/07/2020. Cancer Research UK 17002, retrospectively registered on 24/08/2022.

Evidence for the impact of interventions and medicines reconciliation on problematic polypharmacy in the UK: A rapid review of systematic reviews.

This was a rapid review of systematic reviews (SRs) on problematic polypharmacy (PP) in the UK. The commissioner-defined topics were burden of PP, interventions to reduce PP, implementation activities to increase uptake of interventions, and efficient handover between primary and secondary care to reduce PP. Databases including Medline were searched to June 2019, SR quality was assessed using AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) and a narrative synthesis was undertaken. Except for burden of PP (SRs had to include UK studies), there were no restrictions on country, location of care or outcomes. Nine SRs were included. On burden, three SRs (including six UK studies) found a high prevalence of polypharmacy in long term care. PP was associated with mortality, although unclear if causal, with no information on costs or health consequences. On interventions, six reviews (27 UK studies) found that interventions can reduce PP, but no effects on health outcomes. On handover between primary and secondary care, one review (two UK studies) found medicine reconciliation activities to reduce medication discrepancies at care transitions reduce PP, although the evidence is low quality. No SRs on implementation activities to increase uptake of interventions were found. SR quality was variable, with some concerns regarding meta-analysis methods. Evidence of the extent of PP in the UK, and what interventions to address it are effective in the UK, is limited. Future UK research is needed on the prevalence and consequences of PP, the effectiveness and cost-effectiveness of interventions to reduce PP, and barriers and activities to ensure uptake.

Behavioural modification interventions for medically unexplained symptoms in primary care: systematic reviews and economic evaluation.

BACKGROUND: The term 'medically unexplained symptoms' is used to cover a wide range of persistent bodily complaints for which adequate examination and appropriate investigations do not reveal sufficiently explanatory structural or other specified pathologies. A wide range of interventions may be delivered to patients presenting with medically unexplained symptoms in primary care. Many of these therapies aim to change the behaviours of the individual who may have worsening symptoms. OBJECTIVES: An evidence synthesis to determine the clinical effectiveness and cost-effectiveness of behavioural modification interventions for medically unexplained symptoms delivered in primary care settings was undertaken. Barriers to and facilitators of the effectiveness and acceptability of these interventions from the perspective of patients and service providers were evaluated through qualitative review and realist synthesis. DATA SOURCES: Full search strategies were developed to identify relevant literature. Eleven electronic sources were searched. Eligibility criteria - for the review of clinical effectiveness, randomised controlled trials were sought. For the qualitative review, UK studies of any design were included. For the cost-effectiveness review, papers were restricted to UK studies reporting outcomes as quality-adjusted life-year gains. Clinical searches were conducted in November 2015 and December 2015, qualitative searches were conducted in July 2016 and economic searches were conducted in August 2016. The databases searched included MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE. Updated searches were conducted in February 2019 and March 2019. PARTICIPANTS: Adult participants meeting the criteria for medically unexplained symptoms, including somatoform disorders, chronic unexplained pain and functional somatic syndromes. INTERVENTIONS: Behavioural interventions were categorised into types. These included psychotherapies, exercise-based interventions, multimodal therapies (consisting of more than one intervention type), relaxation/stretching/social support/emotional support, guided self-help and general practitioner interventions, such as reattribution. Evidence synthesis: a network meta-analysis was conducted to allow a simultaneous comparison of all evaluated interventions in a single coherent analysis. Separate network meta-analyses were performed at three time points: end of treatment, short-term follow-up (< 6 months since the end of treatment) and long-term follow-up (≥ 6 months after the end of treatment). Outcomes included physical and psychological symptoms, physical functioning and impact of the illness on daily activities. Economic evaluation: within-trial estimates of cost-effectiveness were generated for the subset of studies where utility values (or quality-adjusted life-years) were reported or where these could be estimated by mapping from Short Form questionnaire-36 items or Short Form questionnaire-12 items outcomes. RESULTS: Fifty-nine studies involving 9077 patients were included in the clinical effectiveness review. There was a large degree of heterogeneity both between and within intervention types, and the networks were sparse across all outcomes. At the end of treatment, behavioural interventions showed some beneficial effects when compared with usual care, in particular for improvement of specific physical symptoms [(1) pain: high-intensity cognitive-behavioural therapy (CBTHI) standardised mean difference (SMD) 0.54 [95% credible interval (CrI) 0.28 to 0.84], multimodal SMD 0.52 (95% CrI 0.19 to 0.89); and (2) fatigue: low-intensity cognitive-behavioural therapy (CBTLI) SMD 0.72 (95% CrI 0.27 to 1.21), relaxation/stretching/social support/emotional support SMD 0.87 (95% CrI 0.20 to 1.55), graded activity SMD 0.51 (95% CrI 0.14 to 0.93), multimodal SMD 0.52 (95% CrI 0.14 to 0.92)] and psychological outcomes [(1) anxiety CBTHI SMD 0.52 (95% CrI 0.06 to 0.96); (2) depression CBTHI SMD 0.80 (95% CrI 0.26 to 1.38); and (3) emotional distress other psychotherapy SMD 0.58 (95% CrI 0.05 to 1.13), relaxation/stretching/social support/emotional support SMD 0.66 (95% CrI 0.18 to 1.28) and sport/exercise SMD 0.49 (95% CrI 0.03 to 1.01)]. At short-term follow-up, behavioural interventions showed some beneficial effects for specific physical symptoms [(1) pain: CBTHI SMD 0.73 (95% CrI 0.10 to 1.39); (2) fatigue: CBTLI SMD 0.62 (95% CrI 0.11 to 1.14), relaxation/stretching/social support/emotional support SMD 0.51 (95% CrI 0.06 to 1.00)] and psychological outcomes [(1) anxiety: CBTHI SMD 0.74 (95% CrI 0.14 to 1.34); (2) depression: CBTHI SMD 0.93 (95% CrI 0.37 to 1.52); and (3) emotional distress: relaxation/stretching/social support/emotional support SMD 0.82 (95% CrI 0.02 to 1.65), multimodal SMD 0.43 (95% CrI 0.04 to 0.91)]. For physical functioning, only multimodal therapy showed beneficial effects: end-of-treatment SMD 0.33 (95% CrI 0.09 to 0.59); and short-term follow-up SMD 0.78 (95% CrI 0.23 to 1.40). For impact on daily activities, CBTHI was the only behavioural intervention to show beneficial effects [end-of-treatment SMD 1.30 (95% CrI 0.59 to 2.00); and short-term follow-up SMD 2.25 (95% CrI 1.34 to 3.16)]. Few effects remained at long-term follow-up. General practitioner interventions showed no significant beneficial effects for any outcome. No intervention group showed conclusive beneficial effects for measures of symptom load (somatisation). A large degree of heterogeneity was found across individual studies in the assessment of cost-effectiveness. Several studies suggested that the interventions produce fewer quality-adjusted life-years than usual care. For those interventions that generated quality-adjusted life-year gains, the mid-point incremental cost-effectiveness ratios (ICERs) ranged from £1397 to £129,267, but, where the mid-point ICER fell below £30,000, the exploratory assessment of uncertainty suggested that it may be above £30,000. LIMITATIONS: Sparse networks meant that it was not possible to conduct a metaregression to explain between-study differences in effects. Results were not consistent within intervention type, and there were considerable differences in characteristics between studies of the same type. There were moderate to high levels of statistical heterogeneity. Separate analyses were conducted for three time points and, therefore, analyses are not repeated-measures analyses and do not account for correlations between time points. CONCLUSIONS: Behavioural interventions showed some beneficial effects for specific medically unexplained symptoms, but no one behavioural intervention was effective across all medically unexplained symptoms. There was little evidence that these interventions are effective for measures of symptom load (somatisation). General practitioner-led interventions were not shown to be effective. Considerable heterogeneity in interventions, populations and sparse networks mean that results should be interpreted with caution. The relationship between patient and service provider is perceived to play a key role in facilitating a successful intervention. Future research should focus on testing the therapeutic effects of the general practitioner-patient relationship within trials of behavioural interventions, and explaining the observed between-study differences in effects within the same intervention type (e.g. with more detailed reporting of defined mechanisms of the interventions under study). STUDY REGISTRATION: This study is registered as PROSPERO CRD42015025520. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 46. See the NIHR Journals Library website for further project information.

The term 'medically unexplained symptoms' is used in relation to individuals who present to their general practitioner with persistent symptoms that cannot easily be explained, even after adequate physical examination and appropriate investigations. Common interventions delivered in primary care tend to be psychological interventions, behaviour therapies or physical exercise therapies. These therapies often aim to change the behaviours of the individual that may make symptoms worse. We conducted systematic reviews of existing evidence to evaluate the effectiveness and acceptability of behavioural interventions delivered in primary care, and a cost-effectiveness analysis to see whether or not they offer good value. Studies measured improvement in outcomes, such as physical or psychological symptoms, or health-related quality of life. There were large differences in the nature of the behavioural interventions delivered and so we grouped them into 'types'. These included intervention types involving exercise (e.g. aerobic or strengthening, or graded activity); different types of psychotherapy, for example cognitive­behavioural therapy; interventions focused on relaxation or social/emotional support; interventions offering education and information; and interventions by general practitioners, for example receiving training on how to implement a behavioural approach to treating medically unexplained symptoms. Statistical analyses were conducted to investigate which, if any, of the intervention types were effective when compared with usual care. Results indicated that some of the behavioural intervention types showed beneficial effects at the end of treatment and at short-term follow-up. In particular, cognitive­behavioural therapy at a higher intensity, and therapies consisting of components of more than one intervention type (i.e. multimodal therapies), showed beneficial effects for specific physical symptoms such as pain, fatigue or bowel symptoms. High-intensity cognitive­behavioural therapy, other types of psychotherapies and interventions focusing on relaxation and social/emotional support showed some beneficial effects on mood outcomes such as depression and anxiety. By long-term follow-up, effects had diminished. More complex measures of symptom load or 'somatisation' showed fewer beneficial effects. We found that no one intervention improved outcomes across all medically unexplained symptoms. However, the results of the statistical analyses should be interpreted with caution. Not only were there differences in the types of behavioural interventions trialled in the included studies, but there were also differences in the characteristics of interventions within the same type. Participants of the studies had a range of symptoms and syndromes, of varying severity and duration. Interventions of the same type varied in how they were delivered, for example the qualifications of the therapist and the contact time spent between therapist and patient. Owing to the limited number of studies in each intervention type, it has not been possible to identify how these differences influenced the results. Interventions delivered by general practitioners themselves did not generally show beneficial effects. However, the relationship between general practitioner and patient was perceived to be important. Patients valued receiving explanations for their symptoms and learning self-management techniques. This was facilitated by good relationships with their health-care practitioner. Health-care practitioners reported a need for training and supervision, but patients reported that the primary care setting was both appropriate and helpful. A successful behavioural intervention should allow a patient and their care provider to maintain a relationship where the patient feels supported. Analyses of the cost-effectiveness of the interventions showed a wide variation in costs. Costs varied between different intervention types, but also between interventions of the same type. Differences in the nature of interventions within the same intervention type, for example whether delivery is to groups or to individuals, make comparisons difficult. Future research should focus on identifying how the relationship between the general practitioner and their patient can influence the effectiveness of a behavioural intervention when it is conducted in the primary care setting. In addition, more research is needed to explore which aspects of the more promising interventions are influencing their effectiveness.

British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland/Public Health England post-polypectomy and post-colorectal cancer resection surveillance guidelines.

These consensus guidelines were jointly commissioned by the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE). They provide an evidence-based framework for the use of surveillance colonoscopy and non-colonoscopic colorectal imaging in people aged 18 years and over. They are the first guidelines that take into account the introduction of national bowel cancer screening. For the first time, they also incorporate surveillance of patients following resection of either adenomatous or serrated polyps and also post-colorectal cancer resection. They are primarily aimed at healthcare professionals, and aim to address:Which patients should commence surveillance post-polypectomy and post-cancer resection?What is the appropriate surveillance interval?When can surveillance be stopped? two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework for the guidelines. The BSG's guideline development process was used, which is National Institute for Health and Care Excellence (NICE) compliant.two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The key recommendations are that the high-risk criteria for future colorectal cancer (CRC) following polypectomy comprise either:two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps This cohort should undergo a one-off surveillance colonoscopy at 3 years. Post-CRC resection patients should undergo a 1 year clearance colonoscopy, then a surveillance colonoscopy after 3 more years.

GENE EXPRESSION PROFILING AND EXPANDED IMMUNOHISTOCHEMISTRY TESTS TO GUIDE SELECTION OF CHEMOTHERAPY REGIMENS IN BREAST CANCER MANAGEMENT: A SYSTEMATIC REVIEW.

OBJECTIVES: The aim of this report was to assess the clinical effectiveness of two Gene expression profiling (GEP) and two expanded immunohistochemistry (IHC) tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer. METHODS: A systematic review of the evidence on clinical effectiveness of OncotypeDX, IHC4, MammaPrint, and Mammostrat, compared with current clinical practice using clinicopathological parameters, in women with early breast cancer was conducted. Ten databases were searched to include citations to May 2016. RESULTS: Searches identified 7,064 citations, of which forty-one citations satisfied the criteria for the review. A narrative synthesis was performed. Evidence for OncotypeDX demonstrated the impact of the test on decision making and there was some support for OncotypeDX predicting chemotherapy benefit. There were relatively lower levels of evidence for the other three tests included in the analysis. MammaPrint, Mammostrat, and IHC4 tests were limited to a small number of studies. Limitations in relation to study design were identified for all tests. CONCLUSIONS: The evidence base for OncotypeDX is considered to be the most robust. Methodological weaknesses relating to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence were identified. Further evidence is required for all of the tests using prospective randomized controlled trial data.

Issues Related to the Frequency of Exploratory Analyses by Evidence Review Groups in the NICE Single Technology Appraisal Process.

BACKGROUND: Evidence Review Groups (ERGs) critically appraise company submissions as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process. As part of their critique of the evidence submitted by companies, the ERGs undertake exploratory analyses to explore uncertainties in the company's model. The aim of this study was to explore pre-defined factors that might influence or predict the extent of ERG exploratory analyses. OBJECTIVE: The aim of this study was to explore predefined factors that might influence or predict the extent of ERG exploratory analyses. METHODS: We undertook content analysis of over 400 documents, including ERG reports and related documentation for the 100 most recent STAs (2009-2014) for which guidance has been published. Relevant data were extracted from the documents and narrative synthesis was used to summarise the extracted data. All data were extracted and checked by two researchers. RESULTS: Forty different companies submitted documents as part of the NICE STA process. The most common disease area covered by the STAs was cancer (44%), and most ERG reports (n = 93) contained at least one exploratory analysis. The incidence and frequency of ERG exploratory analyses does not appear to be related to any developments in the appraisal process, the disease area covered by the STA, or the company's base-case incremental cost-effectiveness ratio (ICER). However, there does appear to be a pattern in the mean number of analyses conducted by particular ERGs, but the reasons for this are unclear and potentially complex. CONCLUSIONS: No clear patterns were identified regarding the presence or frequency of exploratory analyses, apart from the mean number conducted by individual ERGs. More research is needed to understand this relationship.

Vedolizumab for Treating Moderately to Severely Active Crohn's Disease After Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn's disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo-controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naïve to tumour necrosis factor alpha antagonist (anti-TNF-α) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF-α agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6-52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn's disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be £21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-α-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above £30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-α-naïve and anti-TNF-α-failure populations) and in patients who were anti-TNF-α naïve only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company's model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues.